Deprotonative Silylation of Aromatic C-H Bonds Mediated by a Combination of Trifluoromethyltrialkylsilane and Fluoride
A method for the deprotonative silylation of aromatic C-H bonds has been developed using trifluoromethyltrimethylsilane (CF3SiMe3, Ruppert-Prakash reagent) and a catalytic amount of fluoride. In this reaction, CF3SiMe3 is considered to act as a base and a silicon electrophile. This process is highly tolerant to various functional groups on heteroarenes and benzenes. Furthermore, this method can be applied to the synthesis of trimethylsilyl group-containing analogs of TAC-101, which is a bioactive synthetic retinoid with selective affinity for retinoic acid receptor α (RAR-α) binding. We also report further transformations of the silylated products into useful derivatives.
Syntheses of 2,5- and 2,6-Difluoronorepinephrine, 2,5-Difluoroepinephrine, and 2,6-Difluorophenylephrine: Effect of Disubstitution with Fluorine on Adrenergic Activity
Synthetic routes to difluorinated analogs of the adrenergic agonists, norepinephrine (NE), epinephrine (E), and phenylephrine (PE) have been developed.The syntheses were based on elaboration of the ethanolamine side chains from the appropriately polyfunctionalized benzaldehydes.The benzaldehydes were prepared from precursor difluorinated benzenes by sequential regioselective lithiations and reaction with electrophiles to introduce hydroxyl and carboxaldehyde functionalities.Binding and functional assay data demonstrate that the 2,6-difluorinated analogs are relatively inactive at both α- and β-adrenergic receptors.These results are consistent with earlier observations that 2-fluoro substitution of adrenergic agonists decreases α-adrenergic activity whereas 6-fluoro substitution decreases β-adrenergic activity.
Chen, George T.,King, Michael,Gusovsky, Fabian,Creveling, Cyrus R.,Daly, John W.,et al.
p. 3947 - 3955
(2007/10/02)
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